8&#39;4-&#39;3-(5Fluoro-1h-indol-3yl)propyl!-1-piperazinyl!-2-methyl-2h-1,4-benzoxazin-3(4h)-one methanesulfonate with high affinity for the dopamine d2 receptor and the seotonix reuptake site

ABSTRACT

The invention relates to the novel mesylate of a phenylpiperazine derivative of the formula (I). This salt has favourable properties as compared with the free base of this compound.

[0001] The invention relates to the novel phenylpiperazine derivative of the formula (I):

[0002] Patent application No. PCT/EP 00/08090 (not yet published) relates a group of novel phenyl piperazines. The compounds of that group show high affinity for both the dopamine D₂ receptor and the serotonin reuptake site. This combination is useful for the treatment of schizophrenia and other psychotic disorders which enables a more complete treatment of all disease symptoms (e.g. positive symptoms and negative symptoms).

[0003] The compounds show activity as antagonists at dopamine D₂ receptors as they potentially antagonize apomorphine-induced climbing behaviour in mice. The compounds also show activity as inhibitors of serotonin reuptake, as they potentiate 5-HTP induced behaviour in mice.

[0004] The compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g. the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67) and antidepressants or anxiolytics (e.g. suppression of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989, 97: 147-148).

[0005] In contrast to clinically relevant dopamine D₂ receptor antagonists the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal side effects than existing antipsychotic agents.

[0006] The inhibitory activity of serotonin reuptake inherent in these compounds may be responsible for the therapeutic effects observed in behavioural models sensitive to either antidepressants or anxiolytics.

[0007] The compounds can be used for the treatment of affections or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotonergic systems, for example: aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, Parkinson's disease, and in particular schizophrenia and other psychotic disorders.

[0008] It has now been found that the mesylate of the above formula has particularly favourable properties in comparison with the free base (i.e. compound no. 89 of EP 99202710.2).

[0009] This mesylate compound is much better soluable in water than the free base resulting in a good bio-availability.

[0010] The compound has a centre of chirality; both the racemic mixture and the individual enantiomers belong to the invention.

[0011] The compound can be brought into forms suitable for administration by means of suitable processes using auxiliary substances such as liquid and solid carrier materials.

[0012] The free base of compounds can be prepared as described in EP 99202710.2

[0013] The free base can be converted into the mesylate according to processes known per se for salt formation.

[0014] The invention is illustrated by means of the following Example.

EXAMPLE

[0015] 2.0 g (4.7 mmol) of the free base obtainable as described in EP 99202710.2 (compound no. 89) is suspended in 40 ml of methanol. The suspension is warmed to 60° C., and a solution of 0.45 g (4.7 mmol) of methanesulfonic acid in 10 ml of methanol is added in about two minutes. A clear solution is obtained. After stirring for 5 minutes at 60° C. the crystallization begins. The solution is cooled slowly in 60 minutes to 20° C., and stirred at that temperature for 30 minutes. Further cooling to 0° C. in 60 minutes and stirring for 90 minutes is carried out. The solid material is isolated by means of filtration, washed with 5 ml of methanol and dried during a night at 50° C. under reduced pressure. Yield 2.17 g (88%) of white coloured mesylate. 

1. Compound of the formula


2. Pharmaceutical composition for treating CNS disorders, characterized in that it contains the compound of claim 1 as an active ingredient.
 3. Method of treating CNS disorders, characterized in that the compound as claimed in claim 1 is used. 